Mood disorders, including bipolar disorder and depressive disorder, are severe mental illnesses that directly affect over 20% of individuals in the U.S. The pathophysiology of mood disorders is poorly understood, and the treatment options are therefore limited. The long term goal of our research is to understand the pathophysiology and improve the treatment of mood disorders. The objective of this application is to identify a central molecular target in animal brain that is regulated by neural modulators relevant to mood disorders. Based on the accumulating evidence showing that glycogen synthase kinase-3 (GSK3) is an active and highly regulated protein kinase in neural tissues, GSK3 is an intracellular target of neurotrophins involved in mood disorders, the mood stabilizer lithium inhibits GSK3, and we have recently discovered that serotonin, a major mood disorder-related monoamine neurotransmitter, regulates GSK3 in animal brain, we hypothesize that GSK3 is a major protein kinase which activity can be altered by various neural modulators involved in the development and the treatment of mood disorders. Three specific aims will be pursued to test the central hypothesis: Specific Aim 1 will test the hypothesis that mood stabilizing agents, including lithium, divalproate, and lamotrigine, regulate GSK3 in mouse brain through different mechanisms of action. Specific Aim 2 will test the hypothesis that serotonergic modulators used in mood disorders, including serotonin reuptake inhibitor antidepressants and dual-acting antipsychotics, regulate GSK3 in mouse brain. Specific Aim 3 will test the hypothesis that GSK3 activity is abnormally regulated by altered brain activities that simulate what occur in mood disorders, which can be prevented or reversed by mood disorder treatments. These studies will thus use straightforward strategies to conduct clinically relevant research in mood disorders. The proposed research is innovative because it aims to identify the in vivo regulation of GSK3 by various neural modulators relevant to the development and the treatment of mood disorders, which have not to date been thoroughly investigated. This research is expected to provide significant new insight into the pathophysiology and the treatment of mood disorders.